Exposure to hypoxia triggers a variety of adverse effects in the brain that arise from metabolic stress and induce neuron apoptosis. Overexpression of the hypoxia-inducible factor-1α (HIF-1α) is believed to be a major candidate in orchestrating the cell's defense against stress. To test the impact of HIF-1α on apoptosis during chronic hypoxia in vivo, we examined the protective effect of modulating the nitric oxide (NO)/cGMP pathway by sildenafil, a selective inhibitor of phosphodiesterase-5 (PDE-5). Male ICR/CD-1 mice were divided into 3 groups (n = 6/group): normoxic (21% O2), hypoxic (9.5% O2), and hypoxic with sildenafil (1.4-mg/kg intraperitoneal injections daily). At the end of the 8-day treatment period, the mice were euthanized and cerebral cortex biopsies were harvested for analyses. We found that sildenafil: (1) did not significantly alter the hypoxia-induced weight loss and hemoglobin increase, but did augment plasma nitrates+nitrites and the tissue content of cGMP and phosphorylated (P) NO synthase III; (2) reversed the hypoxia-induced neuron apoptosis (terminal deoxynucleotidyl transferase positivity and double-staining immunofluorescence, P = 0.009), presumably through increased bcl-2/Bax (P = 0.0005); and (3) did not affect HIF-1α, but rather blunted the hypoxia-induced increase in P-ERK1/2 (P = 0.0002) and P-p38 (P = 0.004). We conclude that upregulating the NO/cGMP pathway by PDE-5 inhibition during hypoxia reduces neuron apoptosis, regardless of HIF-1α, through an interaction involving ERK1/2 and p38.
Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of HIF-1α signaling / A. Caretti, P. Bianciardi, R. Ronchi, M. Fantacci, M. Guazzi, M. Samaja. - In: EXPERIMENTAL BIOLOGY AND MEDICINE. - ISSN 1535-3702. - 233:10(2008 Jul 18), pp. 1222-1230.
|Titolo:||Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of HIF-1α signaling|
CARETTI, ANNA (Primo)
BIANCIARDI, PAOLA ROSANNA MARIA (Secondo)
GUAZZI, MARCO (Penultimo)
SAMAJA, MICHELE (Ultimo)
|Parole Chiave:||Bcl-2; Chronic hypoxia; HIF-lα; Hypoxia signaling; NO|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||18-lug-2008|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3181/0802-RM-73|
|Appare nelle tipologie:||01 - Articolo su periodico|